1. Field of the Invention
The present invention is directed to devices and methods for administering at least one effective dose of at least one therapeutic substance to at least one of the maxillary sinuses of a patient in need thereof. Alternate embodiments may comprise administration of the at least one effective dose of at least one therapeutic substance to both maxillary sinuses, where the administered therapeutic substance(s) are either the same or differ from sinus to sinus. Still further alternative embodiments may comprise more than an initial effective dose administered to a patient's maxillary sinus(es), so that the therapeutic substance may be delivered over time, thereby requiring a larger dose be deposited within at least one of the maxillary sinuses so that the maxillary sinus(es) serve as a therapeutic substance depot for long-term release to the target structure(s).
2. Description of the Related Art
It is known that intranasal delivery of therapeutic substances to patients pre or post-stroke, or those diagnosed with disorders involving neurological impairments, e.g., Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, spinal cord injury can be an effective treatment for the condition. See, e.g., Reger M A, Watson G S, Green P S, Wilkinson C W, Baker L D, Cholerton B, Fishel M A, Plymate S R, Breitner J C, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70:440-448 (2008).
Intranasal delivery to the upper one-third of the patient's nasal cavity provides a non-invasive method of bypassing the blood-brain barrier (BBB) in order to rapidly deliver therapeutic substances directly to the target organ and/or region. For example, and without limitation, such targeted intranasal administration to the upper one-third of the nasal cavity of a therapeutic substance delivers the substance directly to the brain, spinal cord, lymphatics and the vessel walls of cerebrovasculature for treating and/or preventing central nervous system (CNS) disorders such as Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, brain tumors. This known method allows drugs, therapeutic proteins, polynucleotides, viral vectors and the like, i.e., compounds that do not normally cross the BBB, to be delivered directly to the CNS with minimal systemic exposure.
Thus, intranasal delivery allows specific targeting of therapeutic substance to the CNS. In particular, targeting the upper one-third of the nasal cavity with the therapeutic substance is most effective and efficient in delivering the administered dose to the patient's CNS. This delivery technique, inter alia, is desirable because it avoids a first-pass elimination by the liver and/or kidneys, thereby allowing a lower therapeutic dose to be used, and minimizing systemic exposure to non-target organs, etc., resulting in fewer undesirable or even dangerous side effects.
More general intranasal delivery, generally defined herein as administration of a therapeutic substance to the upper one-third and/or lower two-thirds of a patient's nasal cavity is known to utilize both the olfactory and trigeminal nerves as a conduit to the CNS. Delivery of the therapeutic substance along the olfactory and trigeminal pathways allows the effective bypassing of the BBB. However, the more general intranasal administration or delivery results in some undesirable and potentially dangerous systemic exposure.
It is also known that greater than 98% of small molecule and nearly 100% of large molecule CNS drugs developed by the pharmaceutical industry do not cross the BBB. Intracerebroventricular or intraparenchymal drug administration can directly deliver therapeutics to the brain; however, these methods are invasive, inconvenient, and impractical for the numbers of individuals requiring therapeutic interventions for treating CNS disorders. Intranasal drug administration is a non-invasive and convenient means to rapidly target therapeutics of varying physical and chemical properties to the CNS. The olfactory and trigeminal neural pathways connecting the nasal passages to the CNS are clearly involved in the delivery of therapeutic compounds applied via intranasal administration to the upper third of the nasal cavity. In addition to these neural pathways, perivascular pathways, and pathways involving the cerebrospinal fluid or nasal lymphatics may play a central role in the distribution of therapeutics from the nasal cavity to the CNS. See, e.g., Dhuria, S V, Hanson, L R and Frey, W H II (2010) Journal of Pharmaceutical Sciences 99(4):1654-1673, Intranasal delivery to the central nervous system: mechanisms and experimental considerations. Numerous therapeutics have been delivered to the CNS following intranasal administration, to both the upper third and lower two-thirds of the nasal cavity, and have demonstrated pharmacological effects in animals and in humans.
The intranasal method of drug delivery holds great promise as an alternative to more invasive routes, particularly administration to the upper one-third of the nasal cavity, however, a number of factors limit the efficiency of intranasal delivery to the CNS. Absorption of intranasally applied drugs into the capillary network in the nasal mucosa can decrease the amount of drug available for direct transport into the CNS. Additional factors within the nasal cavity, including the presence of nasal mucociliary clearance mechanisms, metabolizing enzymes, efflux transporters and nasal congestion can also reduce the efficiency of delivery into the CNS. In particular, therapeutic compounds may be absorbed into the blood and/or delivered to peripheral (non-target) tissues, thus reducing delivery of the compound to the target. As a result, the efficacy of administering therapeutic compounds to the lower two-thirds of the nasal cavity with the goal of delivering therapeutics to the CNS is greatly diminished. Further, the efficacy of administering therapeutic compounds to the upper one-third of the nasal cavity as a means to target therapeutics to the CNS could be improved. For example, current methods require a single effective dose be delivered when needed to the upper one-third of the nasal cavity, repeated as necessary per the treatment plan. This requires patient compliance with a repeated application, which is generally less than optimal. In addition, intranasal administration may be somewhat uncomfortable, further diminishing patient compliance. Moreover, general intranasal administration, or even administration to the upper one-third of the patient's nasal cavity, involves the olfactory nerves which innervate some different structures than does the trigeminal nerve. Therefore, intranasal administration cannot target only those structures innervated by the trigeminal nerve.
It is desirable then to provide devices and methods for administering at least one effective dose of at least one therapeutic substance to target at least one structure that is innervated by the trigeminal nerve and/or is in operative or fluid communication with the maxillary sinus. Since the trigeminal nerve passes through the maxillary sinus, the sinus cavity may be used as a repository for at least one therapeutic substance. Alternate embodiments may comprise administration of the at least one effective dose of at least one therapeutic substance to both maxillary sinuses, where the administered therapeutic substance(s) are either the same or differ from sinus to sinus. Still further alternative embodiments may comprise more than an initial effective dose administered to a patient's maxillary sinus(es), so that the therapeutic substance may be delivered over time, thereby requiring a larger dose be deposited within at least one of the maxillary sinuses so that the maxillary sinus(es) serve as a therapeutic substance depot for long-term release to the target structure(s).
Current devices and methods access one or more maxillary sinuses with a catheter for a lavage, e.g., to flush infected sinus areas. These devices only serve to clean out the nasal cavity where the catheter is placed, and only partially reach the sinus with a large volume of fluid flushing the nasal cavity. Thus, these devices are poorly targeted and not designed for purposes of delivering a therapeutic substance to the maxillary sinus cavity. There are also known implantable devices requiring surgery which leads to inflammation in the area and has the potential to lead to infection. Further, none of these methods comprise an effective dose of a therapeutic substance to treat a structure either remote from and in operative communication with the maxillary sinus, e.g., the patient's CNS, or innervated by the trigeminal nerve and thereby in operative communication with the maxillary sinus.
Further, current devices and methods may, via general inhalation methods, enable a very small, i.e., much less than 0.1 milliliter, of the inhaled substance to make its way through the tortuous pathway from the nostril and into the maxillary sinus. To make this journey via inhalation, the therapeutic substance must travel between the lower and middle concha, pass over and into the semilunar hiatus, travel superiorly into the maxillary sinus opening, resist the ciliated action of the ostium/tube passing into the maxillary sinus and ultimately moving into the sinus itself. The vast remainder of the inhaled substance is given to the general system, resulting in unnecessary exposure, poor targeting of subject organs/structures. Thus, a large overdosing of the substance is required in order to provide a therapeutic amount to the subject organ/structure, the remaining dose being delivered to the system with resulting undesirable and often dangerous side effects. The methods and devices of the present invention enable a full effective dose(s) to be deposited directly into the maxillary sinus without any systemic exposure.